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瞬时受体电位通道蛋白4（Trpm4）基因无效会导致心脏肥大和电生理改变。

Trpm4 gene invalidation leads to cardiac hypertrophy and electrophysiological alterations.

作者信息

Demion Marie, Thireau Jérôme, Gueffier Mélanie, Finan Amanda, Khoueiry Ziad, Cassan Cécile, Serafini Nicolas, Aimond Franck, Granier Mathieu, Pasquié Jean-Luc, Launay Pierre, Richard Sylvain

机构信息

INSERM U1046, Université Montpellier1, Université Montpellier2, Montpellier, France.

INSERM U1046, Université Montpellier1, Université Montpellier2, Montpellier, France; CHRU Montpellier, Service de Cardiologie, Montpellier, France.

出版信息

PLoS One. 2014 Dec 22;9(12):e115256. doi: 10.1371/journal.pone.0115256. eCollection 2014.

DOI:10.1371/journal.pone.0115256
PMID:25531103
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4274076/
Abstract

RATIONALE

TRPM4 is a non-selective Ca2+-activated cation channel expressed in the heart, particularly in the atria or conduction tissue. Mutations in the Trpm4 gene were recently associated with several human conduction disorders such as Brugada syndrome. TRPM4 channel has also been implicated at the ventricular level, in inotropism or in arrhythmia genesis due to stresses such as ß-adrenergic stimulation, ischemia-reperfusion, and hypoxia re-oxygenation. However, the physiological role of the TRPM4 channel in the healthy heart remains unclear.

OBJECTIVES

We aimed to investigate the role of the TRPM4 channel on whole cardiac function with a Trpm4 gene knock-out mouse (Trpm4-/-) model.

METHODS AND RESULTS

Morpho-functional analysis revealed left ventricular (LV) eccentric hypertrophy in Trpm4-/- mice, with an increase in both wall thickness and chamber size in the adult mouse (aged 32 weeks) when compared to Trpm4+/+ littermate controls. Immunofluorescence on frozen heart cryosections and qPCR analysis showed no fibrosis or cellular hypertrophy. Instead, cardiomyocytes in Trpm4-/- mice were smaller than Trpm4+/+with a higher density. Immunofluorescent labeling for phospho-histone H3, a mitosis marker, showed that the number of mitotic myocytes was increased 3-fold in the Trpm4-/-neonatal stage, suggesting hyperplasia. Adult Trpm4-/- mice presented multilevel conduction blocks, as attested by PR and QRS lengthening in surface ECGs and confirmed by intracardiac exploration. Trpm4-/-mice also exhibited Luciani-Wenckebach atrioventricular blocks, which were reduced following atropine infusion, suggesting paroxysmal parasympathetic overdrive. In addition, Trpm4-/- mice exhibited shorter action potentials in atrial cells. This shortening was unrelated to modifications of the voltage-gated Ca2+ or K+ currents involved in the repolarizing phase.

CONCLUSIONS

TRPM4 has pleiotropic roles in the heart, including the regulation of conduction and cellular electrical activity which impact heart development.

摘要

原理

TRPM4是一种非选择性的Ca2+激活阳离子通道，在心脏中表达，尤其是在心房或传导组织中。Trpm4基因的突变最近与几种人类传导障碍有关，如Brugada综合征。TRPM4通道也与心室水平有关，涉及变力作用或由于β-肾上腺素能刺激、缺血-再灌注和缺氧复氧等应激导致的心律失常发生。然而，TRPM4通道在健康心脏中的生理作用仍不清楚。

目的

我们旨在利用Trpm4基因敲除小鼠（Trpm4-/-）模型研究TRPM4通道对整体心脏功能的作用。

方法与结果

形态功能分析显示，与Trpm4+/+同窝对照小鼠相比，Trpm4-/-小鼠左心室（LV）出现离心性肥厚，成年小鼠（32周龄）的室壁厚度和腔径均增加。对冷冻心脏切片进行免疫荧光和qPCR分析显示无纤维化或细胞肥大。相反，Trpm4-/-小鼠的心肌细胞比Trpm4+/+小鼠的小，但密度更高。有丝分裂标记物磷酸化组蛋白H3的免疫荧光标记显示，在Trpm4-/-新生期，有丝分裂心肌细胞的数量增加了3倍，提示细胞增生。成年Trpm4-/-小鼠出现多级传导阻滞，体表心电图上PR和QRS间期延长可证明这一点，并经心内探查证实。Trpm4-/-小鼠还表现出Luciani-Wenckebach房室传导阻滞，阿托品注射后这种阻滞减轻，提示阵发性副交感神经亢进。此外，Trpm4-/-小鼠心房细胞的动作电位较短。这种缩短与复极化期涉及的电压门控Ca2+或K+电流的改变无关。

结论

TRPM4在心脏中具有多效性作用，包括对传导和细胞电活动的调节，这会影响心脏发育。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65a7/4274076/40f07d5865b7/pone.0115256.g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65a7/4274076/2e22d586f4c2/pone.0115256.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65a7/4274076/fb27fc500cff/pone.0115256.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65a7/4274076/3a151b43e8df/pone.0115256.g003.jpg
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